So, we talked about how we have five pillars of anti-cancer therapies, and immunotherapy has become one of the most exciting revolutionary in the last few years. So, I'm going to talk more about what is emerging and why are we advancing, and what does it mean as an intensivist, right? We're non-oncologists, so why does it matter to us? Well, the reason is because this is becoming one of the most talked about and highly advanced therapies, not just in cancer, but in a number of different disease states, such as autoimmunity and even dementia, potentially. So, understanding the concept of adaptive immunotherapy, understanding why CAR-T has some limitations, and Dr. Brown talked a lot about some of our toxicities, and then reviewing some of our novel therapies and what are the advantages and definitely potential challenges that we have with those new therapies. So, I have no relevant disclosures. So, cancer immunotherapy, as I said, we're looking at it in a new way. We understand that CAR-T cells have really advanced cancer therapy in a number of different disease states, and what it does is it uses the patient's own immune cells to help fight the cancer cells. So, it causes the cancer cells to die by manipulating the T cells. And the CARs have gone through four different generations already. Again, the goal is to sharpen and strengthen the immune system's inherent cancer-fighting powers. So, the CAR-T cell, as I mentioned, is the one that we know most, but as we move on, we talk about natural killer cells, T cell receptor therapy, and then the tumor-infiltrating lymphocytes, which is what I'll review today. So, why are we moving beyond CAR-T therapy? Well, because when we look at patients, it depends on how much chemotherapy they've had and how receptive their T cells are, and that affects their ex vivo processing. It can be very time-consuming and expensive. It takes a lot to engineer these cells, and it can be patient-specific as well. And then we talked about some of the toxicities, which include CRS and neurotoxicity, hypogammaglobulinemia, and sepsis. Infusion loss is an interesting concept. The cancer cells develop ways to evade the immune system and change the antigens, and so if the antigens are changed, CAR-T cells become ineffective. And the purpose of the CAR-T is to become a living therapy and to continue to fight the cancer cells after the initial infusion, so then this can cause failure of the CAR-Ts and relapse. And then there's potential for GVHD for these off-the-shelf or allogeneic CAR-T cells. So, this is why we're trying to understand new therapies to move ahead with different cancers. So, NK cells, they come from CD34-positive hemopoietic progenitor cells. They represent a portion of our peripheral blood lymphocytes, and they're used for tumor immunosurveillance. It's important because they lack markers characteristic of T and B lymphocytes. They're non-phagocytic. They're constantly replenished, and they have a short half-life. They also mediate target killing through this antibody-dependent cytotoxic cellular therapy or cellular, and they can detect and eliminate cancer cells more effectively, particularly in hematologic malignancies. So, they have these unique killing mechanisms, and the NK cells target the perforin and granzyme release, causing some more apoptosis. Macrophages then mediate phagocytosis and prime the immune cells toward the tumor. NK-T cells have unique features that include T-cell receptor-based CD1-dependent target cell killing, and then our gamma-delta cell effector function is mediated by mechanisms similar to the NK cells. So, the advantage is it can be derived from multiple sources, including pluripotent hematopoietic stem cells, umbilical cord cells, peripheral mononuclear blood cells. It can have a better safety profile. It seems to lack CRS and ICANs and would, again, then lack GVHD. So, that leads to the potential for off-the-shelf allogeneic marketing. The multiple mechanisms for activating cytotoxic activity, and they can be engineered to target diverse antigens. So, that allows for enhanced proliferation, increased infiltration into solid tumors where CAR-T cells have failed in solid tumors because of the antigen specificity, and it can overcome resistant the tumor microenvironment, which has become a challenge to addressing the solid tumors as well. It can cause a more efficient response to achieve that antitumor response. So, some of the challenges is it has low transduction efficiency. It's limited ex vivo expansion potential and reduced persistence, so then it causes less success in solid tumors. Some of the applications may be ovarian cancer, multiple myeloma, and leukemia. And then, moving on to tumor infiltrating lymphocytes, I find this to be very interesting. So, what they do is they take the tumor tissue, and then they extract it. They cause expansion of it, and then it becomes enhanced with IL-2. And with that, it can cause some more toxicity, and that's what I'll focus on here in a minute. The disadvantages, it can be labor-intensive, time-consuming, and expensive. You'll hear a lot about it in melanoma, and there's a product that should become FDA-approved in the near future because of a study that looked at higher disease survival and had a objective immune response based on the RESIST criteria. I won't go through all the details just based on time, but there are a number of TLI therapy trials undergoing in the last 10 years. This is pretty significant when we look at all the different tumors that they're evaluating. And so, what happens with IL-2, so you can have high-dose IL-2 and low-dose IL-2. High-dose IL-2 causes anti-tumor activity. Low-dose IL-2 is where we're going to see it with autoimmunity because it's targeting TH17 response. So with this, it ultimately upregulates the Tregs and then causes some increase of the alpha receptor-mediated innate lymphocyte cell release and cytotoxic effects. And so, that then leads to more stimulation and more tumor immune response. But along these lines, and when you're increasing the eosinophils and some of the cytokines, that leads to some of the toxicity that we would see. And as intensivists, we will 100% see the IL-2 toxicity in our ICU. So the IL-2 toxicity requires ICU monitoring. You need to establish a set of management and protocols for your institution so that you know when to transfer a patient to the ICU, and you work very closely with oncologists for when to hold an IL-2 dose. It is a cumulative and may be refractory over time. So the toxicity includes fever, chills, rigors in almost 100% of patients, constitutional symptoms. It can have profuse diarrhea, causing significant hypovolemia. It can cause rashes and significant electrolyte disturbances and metabolic acidosis. But what leads them to the ICU is shock. Cardiac dysrhythmias, including SVT, AFib, VTAC, renal dysfunction, and then respiratory failure related to volume overload, capillary leak syndrome, and bronchospasm. Neurotoxicity also can occur. Hepatotoxicity usually resolves spontaneously, and then there are other hematologic dysfunction as well. The standard management is what we use to care for those patients, making sure that we exclude any underlying infection, particularly prior to receiving high-dose IL-2, but certainly as they start to decompensate, that there's no underlying infection. T-cell receptor therapies, they, again, use our own T-cells to express these hotspot mutations that are found in cancer. So they may work for solid tumors. They target these specific antigens. And just for an example, this is looking at a KRAS mutation in colorectal cancer that led to regression of visceral mets. Here's another example looking at metastatic pancreatic cancer that was published in the New England Journal of Medicine in a single patient that had refractory metastatic pancreatic cancer. What they did was they used her HLA-specific target and the KRAS. They had preconditioning that was non-myeloablative with cyclophosphamide, and they also prophylactically gave tocilizumab to try to prevent CRS. The patient then received high-dose IL-2. That's to enhance the T-cell proliferation post-infusion. And so the patient had a significant response at six months, which is pretty remarkable. Complications is what we've seen with a number of these therapies, CRS, ICANs, myelosuppression, and then the IL-2 toxicity. The limitations would be that it can only be used in a subset of solid tumors, and most tumors don't have these specific unique markers for the CAR-T to target. Moving on to some other already FDA-approved is the BITE therapy. So by specific T-cell engagers, there's a link between T-cells and specific target antigens that allow for cytotoxic eradication of the cancer cells. It's not MHC-specific and does not require patient-specific processing. So blinitumumab, which is used in BALL, and teclistamab, which is used in multiple myeloma. The downside, of course, is our CRS and our ICANs, along with can cause an infusion reaction. So here are a number of ways that we can see new cells coming up in future directions. And just to be aware of what may be occurring in our ICU. So again, what does this mean for intensivists? Intensivists in IEC trials might reside in the hospital for two to three weeks with continuous monitoring. It requires a high level of coordination and multidisciplinary approach to these patients with good quality control. And clinical trials should have input from intensivists. We work very closely with our oncology team to develop the protocols for these trials, and we need to understand the complications that can occur. So thank you very much.

Immunotherapy

CAR-T cells

NK cells

TILs

toxicities